Gastroschisis for the Gastroenterologist: Updates on Epidemiology, Management, and Outcomes.

Gastroschisis is a common congenital abdominal wall defect, likely influenced by environmental factors in utero, with increasing prevalence in the United States. Early detection of gastroschisis in utero has become the standard with improved prenatal care and screening. There are multiple surgical management techniques, though sutureless closure is being used more frequently. Postoperative feeding difficulty is common and requires vigilance for complications, such as necrotizing enterocolitis. Infants with simple gastroschisis are expected to have eventual catch-up growth and normal development, while those with complex gastroschisis have higher morbidity and mortality. Management requires collaboration amongst several perinatal disciplines, including obstetrics, maternal fetal medicine, neonatology, pediatric surgery, and pediatric gastroenterology for optimal care and long-term outcomes.

Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and an orphan disease with no specific treatment. Most patients with confirmed NEC develop moderate-severe thrombocytopenia requiring one or more platelet transfusions. Here we used our neonatal murine model of NEC-related thrombocytopenia to investigate mechanisms of platelet depletion associated with this disease [K. Namachivayam, K. MohanKumar, L. Garg, B. A. Torres, A. Maheshwari, Pediatr. Res. 81, 817-824 (2017)]. In this model, enteral administration of immunogen trinitrobenzene sulfonate (TNBS) in 10-d-old mouse pups produces an acute necrotizing ileocolitis resembling human NEC within 24 h, and these mice developed thrombocytopenia at 12 to 15 h. We hypothesized that platelet activation and depletion occur during intestinal injury following exposure to bacterial products translocated across the damaged mucosa. Surprisingly, platelet activation began in our model 3 h after TNBS administration, antedating mucosal injury or endotoxinemia. Platelet activation was triggered by thrombin, which, in turn, was activated by tissue factor released from intestinal macrophages. Compared to adults, neonatal platelets showed enhanced sensitivity to thrombin due to higher expression of several downstream signaling mediators and the deficiency of endogenous thrombin antagonists. The expression of tissue factor in intestinal macrophages was also unique to the neonate. Targeted inhibition of thrombin by a nanomedicine-based approach was protective without increasing interstitial hemorrhages in the inflamed bowel or other organs. In support of these data, we detected increased circulating tissue factor and thrombin-antithrombin complexes in patients with NEC. Our findings show that platelet activation is an important pathophysiological event and a potential therapeutic target in NEC.

A Central Role for Lipocalin-2 in the Adaptation to Short-Bowel Syndrome Through Down-Regulation of IL22 in Mice.

BACKGROUND & AIMS: In short-bowel syndrome (SBS), inadequate intestinal adaptation is responsible for the majority of complications, including sepsis, liver failure, and death. In this study, we sought to further delineate the adaptive response to identify potential therapeutic targets. METHODS: We performed a 75% small-bowel resection (SBR) or sham operation on C57Bl/6J wild-type (WT), lipocalin-2 (LCN2)-/-, and interleukin 22 (IL22)-/- mice. Exogenous IL22 was administered to SBR WT mice. Cecal fecal matter from SBR WT and SBR LCN2-/- mice were transplanted into germ-free mice. Intestinal permeability, inflammation, proliferation, and the microbiome were evaluated 1 week after surgery. CD4+IL22+ laminal propria lymphocytes were sorted by flow cytometry. Naïve T cells were polarized to T-helper cells with or without LCN2. RESULTS: A 75% SBR in a mouse re-creates the increased intestinal permeability, enterocyte proliferation, and intestinal dysbiosis seen in SBS. LCN2 expression increases after 75% SBR, and this increase can be abrogated with broad-spectrum antibiotic treatment. LCN2-/- mice have less intestinal inflammation, increased IL22 expression, and greater adaptation as evidenced by less intestinal permeability, increased carbohydrate enzyme expression, less weight loss, and less dysbiosis after 75% SBR than WT mice. The proinflammatory and anti-adaptive effects of LCN2 can be transferred to germ-free mice via a fecal transplant. Administration of exogenous IL22 improves adaptation and restores the normal microbiome after 75% SBR in WT mice. CONCLUSIONS: LCN2 promotes inflammation and slows intestinal adaptation through changes in the microbiome and IL22 inhibition in a mouse SBS model. Strategies to reduce LCN2 may offer novel therapeutic approaches to enhance adaptation in SBS.

Cost-effectiveness Analysis of Feeding Guidelines for Infants Following Intestinal Surgery.

OBJECTIVE: The aim of the study was to determine the cost-effectiveness of postoperative feeding guidelines to reduce complications in infants with intestinal surgery compared to standard feeding practices. METHODS: Using outcomes from a cohort study, Markov models from health care and societal perspectives simulated costs per hospitalization among infants fed via guidelines versus standard practice. Short-term outcomes included intestinal failure-associated liver disease, necrotizing enterocolitis after feeding, sepsis, and mortality. Effectiveness was measured as length of stay. The incremental cost-effectiveness ratios (ICER) compared cost over length of stay. Univariate and multivariate probabilistic sensitivity analyses with 10,000 Monte Carlo Simulations were performed. A second decision tree model captured the cost per quality-adjusted life years (QALYs) using utilities associated with long-term outcomes (liver cirrhosis and transplantation). RESULTS: In the hospital perspective, standard feeding had a cost of $31,258,902 and 8296 hospital days, and the feeding guidelines had a cost of $29,295,553 and 8096 hospital days. The ICER was $-9832 per hospital stay with guideline use. More than 90% of the ICERs were in the dominant quadrant. Results were similar for the societal perspective. Long-term costs and utilities in the guideline group were $2830 and 0.91, respectively, versus $4030 and 0.90, resulting in an ICER of $-91,756/QALY. CONCLUSION: In our models, feeding guideline use resulted in cost savings and reduction in hospital stay in the short-term and cost savings and an increase in QALYs in the long-term. Using a systematic approach to feed surgical infants appears to reduce costly complications, but further data from a larger cohort are needed.

Postoperative Feeding Guidelines Improve Outcomes in Surgical Infants.

BACKGROUND: Early introduction of enteral nutrition (EN) in postoperative infants improves intestinal adaptation, reducing the risk of intestinal failure-associated liver disease (IFALD). Our objective was to determine whether guideline use reduces feeding variability and improves outcomes in the neonatal intensive care unit (NICU). METHODS: In a cohort study, surgical infants at risk for IFALD were evaluated pre and post implementation of feeding guidelines at 2 NICUs. A total of 167 guideline infants (2013-2018) were compared with 242 historical controls (2007-2013). Adherence was measured with timing and volume of initial postoperative feed. Primary outcomes were IFALD incidence and time to reach 50% and 100% of energy from EN. Secondary outcomes were parenteral nutrition (PN) days, postoperative necrotizing enterocolitis (NEC), central line-associated bloodstream infection (CLABSI), and length of stay (LOS). RESULTS: Moderate IFALD decreased from 32% to 20% (P = .005) in the guideline group. Time to achieve 50% and 100% energy from EN was decreased from medians of 8 to 5 and 28 to 21 days, respectively (P < .001). There was an overall decrease in PN use from 41 to 29 days (P = .002), CLABSI incidence from 25% to 5% (P < .001), and LOS from 70 to 53 days (P = .030). Once stratified by diagnosis, infants with NEC showed greatest improvement and reduction in IFALD from 67% to 42% (P = .045). With no difference in postoperative NEC (P = .464). CONCLUSION: Early standardized postoperative EN guidelines in intestinal-surgery infants was associated with improved outcomes, including faster achievement of feeding goals and reduced IFALD severity, especially in infants with NEC.

Use of Breast Milk and Other Feeding Practices Following Gastrointestinal Surgery in Infants.

OBJECTIVES: The aim of the study was to characterize the enteral feeding practices in infants after gastrointestinal surgery. METHODS: We performed a retrospective analysis of infants who underwent intestinal surgery at age <6 months who survived to be fed enterally between January 2012 and June 2017. Demographics, surgical characteristics, feeding practices, and growth-related outcomes during hospitalization, discharge, and follow-up (3, 6, and 12 months) were obtained from the electronic medical records. Descriptive statistics compared infants by their initial diagnosis. RESULTS: We reviewed 111 infants: necrotizing enterocolitis (NEC) = 21, gastroschisis = 28, atresia = 27, spontaneous intestinal perforation (SIP) = 18, and other diagnoses = 17. Most infants (77%) received mother's milk (MM) as the first postoperative feed, but this differed by diagnosis (P = 0.004). Donor milk was used in 11%, most commonly in infants with NEC and SIP. Infants with NEC were least likely to continue MM in the hospital (7%, P = 0.0014) and were more likely to receive elemental formula. Only 44% of infants received MM at discharge. After 1 year, 25% were fed MM. The majority of infants were discharged with feeding tubes (nasogastric: 35%, gastric: 23%). Although all groups had acceptable weights at discharge, infants with NEC (z score: -1.8) and SIP (z score: -1.1) showed growth failure at 3 months (z scores: -3.3, -3.2, respectively, P < 0.0001), but had appropriate gain by 1 year (z scores: -1.1, -1.7, respectively). CONCLUSIONS: Despite most infants receiving MM in the early postoperative period, <50% at discharge and only 33% at 1-year still received MM. Weight gain after discharge in infants with NEC and SIP warrants close monitoring.

Postoperative Enteral Nutrition Guidelines Reduce the Risk of Intestinal Failure-Associated Liver Disease in Surgical Infants.

OBJECTIVE: To assess the effectiveness of postoperative feeding guidelines in reducing the incidence and severity of intestinal failure-associated liver disease (IFALD) among infants. STUDY DESIGN: Two cohorts of infants <6 months old undergoing intestinal surgery were compared: preguideline (retrospective data from 2007 to 2013; n = 83) and postguideline (prospective data from 2013 to 2016; n = 81). The guidelines included greater initial enteral nutrition volumes of 20 mL/kg/d and daily feeding advancement if tolerated. The primary outcomes were incidence of IFALD (peak direct bilirubin [DB] >2 mg/dL) and severity (DB >5 mg/dL for moderate-severe). Multiple logistic regression was used to determine the odds of developing IFALD. Other outcomes were time to reach 50% and 100% goal calories from enteral nutrition and the incidence of necrotizing enterocolitis after feeding. RESULTS: The incidence of IFALD decreased from 71% to 51% (P = .031), and median peak DB decreased from 5.7 to 2.4 mg/dL (P = .001). After adjusting for diagnosis and prematurity, the odds of developing IFALD of any severity were reduced by 60% (OR 0.40, 95% CI 0.20-0.85), and the odds of developing moderate-to-severe IFALD were reduced by 72% (OR 0.28, 95% CI 0.13-0.58) with guideline use. Time to reach 50% enteral nutrition decreased from a median of 10 to 6 days (P = .020) and time to reach 100% enteral nutrition decreased from 35 to 21 days (P = .035) with guideline use. The incidence of necrotizing enterocolitis after initiating enteral nutrition did not change (5% vs 9%, P = .346). CONCLUSIONS: Implementation of feeding guidelines reduced time to reach feeding goals, significantly reducing IFALD incidence and severity.